CN102219748A - Amorphous Ambrisentan and preparation method thereof - Google Patents
Amorphous Ambrisentan and preparation method thereof Download PDFInfo
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- CN102219748A CN102219748A CN2011101140725A CN201110114072A CN102219748A CN 102219748 A CN102219748 A CN 102219748A CN 2011101140725 A CN2011101140725 A CN 2011101140725A CN 201110114072 A CN201110114072 A CN 201110114072A CN 102219748 A CN102219748 A CN 102219748A
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Abstract
The invention provides amorphous (+)-(2S)-2-[(4,6-diemthyl pyrimidine-2-yl)oxy]3-methyoxy-3,3-diphenylpropanoic acid (Ambrisentan). The graph of the Ambrisentan is detected by virtue of X-ray powder diffraction. The invention further provides a preparation method of the amorphous Ambrisentan. The preparation method comprises the following steps: dissolving crystalline Ambrisentan solid into one solvent or a mixture of multiple solvents so as to prepare a solution, or directly preparing an Ambrisentan reaction solution; and carrying out spray drying on the solution, spraying into water and then stirring so that the amorphous Ambrisentan is separated out, or directly pouring the solution into water so as to collect the amorphous Ambrisentan. The amorphous Ambrisentan in the invention is easier to be prepared into medicament preparations. Compared with the Ambrisentan serving as a water-indissoluble medicament for preparing the preparations, the amorphous Ambrisentan in the invention has a good dissolution release behavior. And simultaneously, the preparation method of the amorphous Ambrisentan is easy to industrialize and has strong production adaptability.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of unformed (+)-(2S)-2-[(4,6-dimethyl pyrimidine-2-yl) the oxygen base]-3-methoxyl group-3, the 3-henyl propionic acid (An Beishengtan, Ambrisentan) and preparation method thereof.
Background technology
An Beishengtan is a kind of effective as selective endothelin-receptor antagonists, and the vasoconstriction due to can potent inhibition endothelin suppresses pulmonary artery pressure and raises, and do not cause the rising of liver transaminase level.An Beishengtan is by U.S. Gilid Science Co. (GileadScience) development, is used for the treatment of pulmonary hypertension by the FDA approval in 2007, to improve patient's motor capacity, improves quality of life.Trade(brand)name Letairis and Volibris.
An Beishengtan, chemical name (+)-(2S)-2-[(4,6-dimethyl pyrimidine-2-yl) the oxygen base]-3-methoxyl group-3, the 3-henyl propionic acid, molecular formula is shown in (I)
(Ⅰ)
As everyone knows, solid chemical material can be divided into crystalline state, unformed shape and eutectic attitude form.The different existences of same solid pharmaceutical often have different physico-chemical properties, as dissolving properties and dissolution rate etc.The existence of medicine and polymorphous research have epochmaking meaning to stability in the assurance pharmaceutical production storage process and the safety and effectiveness in the clinical use.The existence of medicine is relevant with drug molecular structure with crystal formation, and crystallization method is relevant during simultaneously also with preparation.At present existing two pieces of inventions about An Beishengtan crystal formation and preparation method thereof.
WO2010091877 discloses a kind of crystal formation of An Beishengtan, its with the X-ray powder diffraction collection of illustrative plates of spending 2 θ and representing 8.9,12.3,17.9,26.9,11.1,13.1,14.1,15.2,18.2,20.6 ± 0.2 has characteristic peak.
WO2011004402 discloses a kind of An Beishengtan crystal formation, its with the X-ray powder diffraction collection of illustrative plates of spending 2 θ and representing 7.462,8.239,11.781,12.703,13.587,14.842,16.703,17.660,18.120,18.740,20.518,21.741,22.722,24.139,25.221,26.641,27.521,30.860,7.980,8.781,12.08,12.999,14.499,15.100,17.441,17.939,18.499,20.120,2 1.499,22.261,22.959,24.701,25.461 27.241,37.440 ± 0.2 has characteristic peak.
Summary of the invention
One object of the present invention is to provide a kind of unformed (+)-(2S)-2-[(4,6-dimethyl pyrimidine-2-yl) oxygen base]-3-methoxyl group-3,3-henyl propionic acid (An Beishengtan, Ambrisentan), its X-ray powder diffraction is seen accompanying drawing 1 and accompanying drawing 2, the unformed An Beishengtan that the present invention obtains is superior in quality, and HPLC detects purity and can reach more than 99%.
Another object of the present invention has provided unformed An Beishengtan solid preparation method, technology simple possible, favorable reproducibility.
A further object of the present invention has provided and has contained unformed An Beishengtan solid pharmaceutical composition.
For achieving the above object, the invention provides following technical scheme:
A kind of unformed An Beishengtan is characterized in that it is to exist with unformed form that this solid detects through the X-ray powder diffraction, and it has the unformed X-ray powder diffraction pattern of the An Beishengtan shown in Figure of description 1 and the accompanying drawing 2; Constitutional features with the nmr spectrum shown in the Figure of description 3; Have the DSC curve shown in the Figure of description 4, exothermic peak is about 155 ℃ (± 2 ℃) and 179 ℃ (± 2 ℃), and endothermic peak is about 173 ℃ (± 2 ℃).
The present invention further discloses the preparation method of unformed An Beishengtan, it is characterized in that carrying out according to the following steps:
1. crystalline An Beishengtan is dissolved in one or more mixed solvents and makes solution; Or the reaction soln of preparation An Beishengtan.
2. step solution 1. adopted spraying drying, be sprayed to stir in the water and separate out or directly pour in the water and separate out, collect unformed An Beishengtan then; Wherein spray drying soln concentration is 0.1%～20%; Spray-dired inlet temperature is 50～120 ℃, and temperature out is 30～100 ℃.The preferably spray drying strength of solution is 5～15%.Spray-dired gas is nitrogen, nitrogen-enriched air By, argon gas or carbonic acid gas.Wherein said be sprayed in the water stir separate out or directly pour into the temperature of separating out in the water be 0 ℃ to room temperature.
Preparation method of the present invention, wherein said solvent refers to one or more mixed form organic solvents in alcohols, ketone, halo alkanes, ester class, oxygen heterocyclic ring class, the acetonitrile, also or the mixed form of these organic solvents and water.Alcohols wherein is one or more mixed forms in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol and the isopropylcarbinol.
Wherein said ketone is acetone or butanone; The halo alkanes is chloroform or methylene dichloride; The ester class is ethyl acetate or butylacetate; The oxygen heterocyclic ring class is dioxane or tetrahydrofuran (THF).
A unformed An Beishengtan solid of typical case of the present invention preparation method is: crystalline An Beishengtan 5g is dissolved in the 100mL ethanol makes solution, with mini spray-dryer (B-290 type) spraying drying, the inlet temperature of spraying drying instrument is controlled at 90-92 ℃, temperature out is 65-67 ℃, uses nitrogen.Collect solid, obtain unformed An Beishengtan 3.5g of the present invention.
Another typical unformed An Beishengtan solid preparation method of the present invention is: crystalline An Beishengtan 5g is dissolved in the 50ml ethanol makes solution, spray to stir in the water of this solution to 10 ℃ and separate out, filter, drying obtains unformed An Beishengtan 4.3 g of the present invention.
Another typical unformed An Beishengtan solid preparation method of the present invention is: crystalline An Beishengtan 5g is dissolved in the ethanol of 50mL and makes solution, this solution directly poured in 0 ℃ the water and separate out, stir a little, filter, drying obtains described unformed An Beishengtan 4.3 g of this patent.
Another typical unformed An Beishengtan solid preparation method of the present invention is: according to the method for reference example 2 with (S)-2-hydroxyl-3-methoxyl group-3,3-henyl propionic acid 4g and 4,6-dimethyl-2-methylsulfonyl pyrimidine 2.95g, in hydrogen sodium and tetrahydrofuran (THF) 27mL in 0 ℃ of reaction, after reaction is finished, add activated carbon treatment, filter, obtain containing the reaction soln of An Beishengtan.This reaction solution poured in the 100mL0.5 mol/L aqueous hydrochloric acid separate out, stir promptly a little and filter, the massive laundering solid is to neutral, and vacuum-drying obtains unformed An Beishengtan solid 3.4g of the present invention
Unformed An Beishengtan solid (Ambrisentan) or its pharmaceutical composition of the present invention's preparation have following feature:
1.X-the ray powder diffraction detected result is seen accompanying drawing 1 and accompanying drawing 2:
Instrument: Japanese D/max2500 type X-ray diffractometer of science;
Target: Cu-K а radiation (λ=1.5405), 2 θ sweep limit: 0-50 °
Step angle: 0.04 ℃
Computing time: 0.5 second
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 ℃/min
Filter disc: graphite monochromator
An Beishengtan solid X-ray powder diffraction detection of the present invention is shown as unformed, sees accompanying drawing 1 and accompanying drawing 2.
2, dsc (DSC) analysis is seen accompanying drawing 4:
Instrument model and test condition: METTLER TOLEDO DCC822 differential scanning calorimeter; Temperature range: 40 ~ 200 ℃; Temperature rise rate: 10 ℃/min.
Analytical results shows: An Beishengtan solid DSC of the present invention shows that exothermic peak is about 155 ℃ (± 2 ℃) and 179 ℃ (± 2 ℃), and endothermic peak is about 173 ℃ (± 2 ℃), sees accompanying drawing 4.
3,
1HNMR detects and sees accompanying drawing 3:
Instrument: BRUKER AV400 NMR; Solvent: DMSO-d
6
An Beishengtan solid of the present invention
1The HNMR characteristic peak is: δ=2.33 (S, 6H, CH
3), 3.36 (S, 3H, OCH3), 6.12 (S, lH, CH), 6.93 (S, 1H, pyrimidine-H), 7.18～7.33 (Ar-H), 12.48 (m, 1H COO-H), see accompanying drawing 3 for m, 10H.
4, contain unformed An Beishengtan solid pharmaceutical composition dissolution determination result of the present invention:
Detection method: two appendix XC of Chinese Pharmacopoeia version in 2010, second method, 50 commentaries on classics/min.
The phosphate buffered saline buffer of dissolution medium: pH5.0.
Control sample: contain crystallinity An Beishengtan, adopt the pharmaceutical composition of embodiment 22 same procedure preparation, specification: 2.5mg according to reference example 1 preparation.
The dissolution data tabulation:
Data presentation unformed An Beishengtan pharmaceutical composition of the present invention has good stripping release behavior.
The present invention further discloses and contain the pharmaceutical composition that the unformed An Beishengtan solid for the treatment of significant quantity and one or more pharmaceutical carriers are formed.Wherein said composition is oral preparations or injection, the preferred oral preparation.For example tablet, capsule, granule, oral liquid or the like.
One or more pharmaceutical carriers of the present invention comprise: thinner, disintegrating agent, solvent, stablizer, tackiness agent and lubricant or the like.Wherein thinner includes but not limited to starch, Microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose, low molecular dextran, sodium-chlor or N.F,USP MANNITOL or the like.Described tackiness agent includes but not limited to water, ethanol, starch slurry, syrup, gelatin, methylcellulose gum, Vltra tears, Xylo-Mucine, sodium alginate or polyvinylpyrrolidone etc.Described lubricant includes but not limited to Magnesium Stearate, stearic acid, sodium stearyl fumarate etc.Described disintegrating agent includes but not limited to starch, sodium starch glycolate, citric acid, sodium bicarbonate and low-substituted hydroxypropyl cellulose etc.Described stablizer comprises but is not limited to BHA, BHT, vitamins C, metal chelator EDTA-2Na or the like.
The present invention further discloses the unformed An Beishengtan solid that obtains with above-mentioned preparation method as activeconstituents in the application aspect the preparation treatment pulmonary hypertension medicine.The unformed An Beishengtan solid that the present invention found has and identical purposes and the result of treatment of this known An Beishengtan solid chemical compound itself.
The positively effect that the unformed An Beishengtan solid of the present invention's preparation is had is:
(1) unformed An Beishengtan is easier to make pharmaceutical preparation, improves the absorption of medicine.The behavior that has stripping preferably to discharge when making pharmaceutical preparation as poorly water soluble drugs than crystallinity An Beishengtan.Unformed An Beishengtan preparation method of the present invention is easy to industrialization simultaneously, and production adaptability is strong.
(2) the unformed An Beishengtan solid of the present invention's preparation, it has the quality height demonstrating valuable characteristic aspect stripping and the preparation preparation, and solubleness is good, is beneficial to advantages such as absorption.
Description of drawings:
The unformed An Beishengtan solid of Fig. 1 (Ambrisentan) X-ray powder diffraction;
The unformed An Beishengtan solid of Fig. 2 (Ambrisentan) X-ray powder diffraction;
Fig. 3 is unformed An Beishengtan solid
1The HNMR collection of illustrative plates;
Fig. 4 is unformed An Beishengtan solid DSC graphic representation.
Embodiment:
The present invention is described further below in conjunction with embodiment, makes this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits the scope of the invention by any way.
Reference example 1
According to Chinese Journal of Pharmaceuticals 2010,41 (1), method described in the P1-3, preparation crystallinity An Beishengtan.
Reference example 2
(S)-and 2-hydroxyl-3-methoxyl group-3,3-henyl propionic acid 4g and 4,6-dimethyl-2-methylsulfonyl pyrimidine 2.95g in 0 ℃ of reaction, after reaction is finished, add activated carbon treatment in hydrogen sodium and tetrahydrofuran (THF) 27mL, filter the reaction soln that obtains containing An Beishengtan.
Embodiment 1
Crystallinity An Beishengtan 1g is dissolved under room temperature in the 100mL methyl alcohol, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 80-85 ℃, temperature out 50-55 ℃, is used nitrogen.Collect the honest toner powder solid 0.7g of An Beisheng of the present invention, it is 99.93% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Embodiment 2
Crystallinity An Beishengtan 10g is dissolved under room temperature in the 100mL ethanol, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 100-102 ℃, temperature out 85-90 ℃, is used nitrogen.Collect the honest toner powder solid 6.9g of An Beisheng of the present invention, it is 99.88% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 5g is dissolved under room temperature in the 100mL acetone, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 68-70 ℃, temperature out 45-50 ℃, is used nitrogen.Collect the honest toner powder solid 3.5g of An Beisheng of the present invention, it is 99.93% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Embodiment 4
Crystallinity An Beishengtan 6g is dissolved under room temperature in 36mL methyl alcohol and the 4mL water, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 70-72 ℃, temperature out 40-45 ℃, is used nitrogen.Collect the honest toner powder solid 4.2g of An Beisheng of the present invention, it is 99.92% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Embodiment 5
Crystallinity An Beishengtan 4g is dissolved under room temperature in 10mL Virahol and the 20mL dioxane, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 95-92 ℃, temperature out 65-70 ℃, is used argon gas.Collect the honest toner powder solid 2.8g of An Beisheng of the present invention, it is 99.91% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Embodiment 6
Crystallinity An Beishengtan 4g is dissolved under room temperature in 5mL ethyl acetate and the 15mL methyl alcohol, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 80-82 ℃, temperature out 56-60 ℃, is used argon gas.Collect the honest toner powder solid 2.8g of An Beisheng of the present invention, it is 99.91% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 1g is dissolved under room temperature in 500mL methylene dichloride and the 500mL methyl alcohol, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 90-85 ℃, temperature out 60-55 ℃, is used nitrogen.Collect honest toner powder solid 0.7 g of An Beisheng of the present invention, it is 99.91% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 4g is dissolved under room temperature in 10mL methyl alcohol and the 20mL Virahol, the clear soln of gained with mini spray-dryer (B-290 type) spraying drying, temperature in 90-85 ℃, temperature out 60-55 ℃, is used nitrogen.Collect the honest toner powder solid 2.8g of An Beisheng of the present invention, it is 99.91% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 6g is dissolved in the 40mL acetone under room temperature, is sprayed in the water under 4 ℃, stirring is separated out, and filters, and drying obtains An Beishengtan solid 5.1g of the present invention, and it is 99.90% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 4g is dissolved in the 80mL methyl alcohol under room temperature, is sprayed in the water under 6 ℃, stirring is separated out, and filters, and drying obtains An Beishengtan solid 3.2g of the present invention, and it is 99.90% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 4g is dissolved in the 20mL ethanol under room temperature, is sprayed in the water under 4 ℃, stirring is separated out, and filters, and drying obtains An Beishengtan solid 3.4g of the present invention, and it is 99.91% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 2.5g is dissolved under room temperature in 20mL Virahol and the 5mL methyl alcohol, is sprayed in the water under 0 ℃, stirring is separated out, filter, drying obtains An Beishengtan solid 2.1g of the present invention, it is 99.90% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 4g is dissolved in the 20mL methyl alcohol under room temperature, pours in the 100mL water and separate out, stir promptly a little and filter, vacuum-drying, obtain An Beishengtan solid 3.4g of the present invention, it is 99.90% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 2g is dissolved in the 20mL ethanol under room temperature, pours in the 100mL water and separate out, stir promptly a little and filter, vacuum-drying, obtain An Beishengtan solid 1.7g of the present invention, it is 99.90% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Crystallinity An Beishengtan 2g is dissolved under room temperature in 10mL dioxane and the 10mL Virahol, pour in the 100mL water and separate out, stir promptly a little and filter, vacuum-drying, obtain An Beishengtan solid 1.7g of the present invention, it is 99.90% that HPLC measures the ee value, fusing point 178-180 ℃ (fusion and decomposition).
Embodiment 16
Crystallinity An Beishengtan 2g is dissolved in the 20mL acetone under room temperature, pours in the 100mL water and separate out, stir promptly a little and filter, vacuum-drying, obtain An Beishengtan solid 1.7g of the present invention, it is 99.90% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Embodiment 17
Crystallinity An Beishengtan 2g is dissolved under room temperature in 15mL methyl alcohol and the 5mL water, pours in the 100mL water and separate out, stir promptly a little and filter, vacuum-drying, obtain An Beishengtan solid 1.7g of the present invention, it is 99.90% that HPLC measures the ee value, fusing point 177-179 ℃ (fusion and decomposition).
Embodiment 18
The solution that contains An Beishengtan with reference example 2 acquisitions, be sprayed in the 0.5mol/L aqueous hydrochloric acid of the 100mL under 6 ℃, stirring is separated out, filter, the massive laundering solid is to neutral, and drying obtains An Beishengtan solid 2.5g of the present invention, it is 96.90% that HPLC measures the ee value, fusing point 176-178 ℃ (fusion and decomposition).
Embodiment 19
The solution that contains An Beishengtan with reference example 2 acquisitions, pour in the 0.5mol/L aqueous hydrochloric acid of 100mL and separate out, stir promptly a little and filter, the massive laundering solid is to neutral, vacuum-drying, obtain An Beishengtan solid 2.5g of the present invention, it is 96.90% that HPLC measures the ee value, fusing point 176-178 ℃ (fusion and decomposition).
Embodiment 20
Unformed An Beishengtan solid 10g, with sucrose 30g, talcum powder 1g, Microcrystalline Cellulose 90g, sodium bicarbonate 25g, silicon-dioxide 0.5 g, sodium stearyl fumarate 1g, mixing, compressing tablet, the bag film-coat is made 1000.
Embodiment 21
Unformed An Beishengtan solid 5g adds EudragitEPO 24.4g, secondary calcium phosphate 72.8g, starch 42.8g, sodium bicarbonate 1.1g, mixing, pure water is granulated, drying, talcum powder 1.4g, sodium stearyl fumarate 6.54g, silica 1 .4g mixes, compressing tablet, and the bag film-coat is made 1000.
Embodiment 22
Unformed An Beishengtan solid 2.5g adds EudragitE100 24.4g, secondary calcium phosphate 72.8g, sodium starch glycolate 42.8g, sodium bicarbonate 1.1g, mixing, pure water is granulated, and drying adds Magnesium Stearate 0.14g, talcum powder 2.8g, sodium laurylsulfate 6.4g mixes, compressing tablet, the bag film-coat is made 1000.
Owing to described the present invention with specific embodiment, the technician who is proficient in this technology can make amendment and the equivalence change to it, and this is understood to include within the scope of the present invention.
Claims (10)
1. a unformed An Beishengtan is characterized in that it is to exist with unformed form that this solid detects through the X-ray powder diffraction, and it has the unformed X-ray powder diffraction pattern of the An Beishengtan shown in Figure of description 1 and the accompanying drawing 2; Constitutional features with the nmr spectrum shown in the Figure of description 3.
2. the preparation method of the described unformed An Beishengtan of claim 1 is characterized in that carrying out according to the following steps:
1. crystalline An Beishengtan is dissolved in one or more mixed solvents and makes solution; Or the reaction soln of preparation An Beishengtan;
2. step solution 1. adopted spraying drying, be sprayed to stir in the water and separate out or directly pour in the water and separate out, collect unformed An Beishengtan then; Wherein spray drying soln concentration is 0.1%～20%; Spray-dired inlet temperature is 50～120 ℃, and temperature out is 30～100 ℃.
3. the described preparation method of claim 2, wherein spray drying soln concentration is 5～15%.
4. the described preparation method of claim 2, wherein said solvent refers to the mixed form of one or more organic solvents in alcohols, ketone, halo alkanes, ester class, oxygen heterocyclic ring class, the acetonitrile, also or the mixed form of these organic solvents and water.
5. the described solvent of claim 4, alcohols wherein is one or more mixed forms in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol and the isopropylcarbinol.
6. the described solvent of claim 4, wherein said ketone is acetone or butanone; The halo alkanes is chloroform or methylene dichloride; The ester class is ethyl acetate or butylacetate; The oxygen heterocyclic ring class is dioxane or tetrahydrofuran (THF).
7. the described preparation method of claim 2, wherein spray-dired gas is nitrogen, nitrogen-enriched air By, argon gas or carbonic acid gas.
8. the described preparation method of claim 2, wherein said be sprayed to stir in the water separate out or directly pour into the temperature of separating out in the water be 0 ℃ to room temperature.
9. pharmaceutical composition, it contains the defined unformed An Beishengtan of the claim 1 for the treatment of significant quantity and one or more pharmaceutical carriers.
10. the described pharmaceutical composition of claim 9, composition wherein is an oral preparations.
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| CN103919747A (en) * | 2014-04-22 | 2014-07-16 | 天津红日药业股份有限公司 | Ambrisentan tablet composition and preparation method thereof |
| CN109320464A (en) * | 2018-10-07 | 2019-02-12 | 威海贯标信息科技有限公司 | A kind of purification process of small grain size ambrisentan |
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| CN103772292A (en) * | 2012-10-23 | 2014-05-07 | 天津康鸿医药科技发展有限公司 | Ambrisentan-DMSO co-crystal, preparation method and application thereof |
| CN103772292B (en) * | 2012-10-23 | 2015-12-16 | 天津康鸿医药科技发展有限公司 | A kind of ambrisentan DMSO cocrystallization thing and its preparation method and application |
| CN103919747A (en) * | 2014-04-22 | 2014-07-16 | 天津红日药业股份有限公司 | Ambrisentan tablet composition and preparation method thereof |
| CN109320464A (en) * | 2018-10-07 | 2019-02-12 | 威海贯标信息科技有限公司 | A kind of purification process of small grain size ambrisentan |
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